Three factors have been implicated in the pathogenesis of anemia of advanced malignancy; (1) impaired release of iron from the reticuloendothelial system, (2) a modest decrease in red cell survival, and most importantly, (3) failure of the bone marrow to adequately increase red blood cell production. The objective of this proposal is to elucidate the mechanism for the relative marrow failure in the anemia of malignancy. In preliminary studies, using an in-vitro marrow culture technique, we have found a subnormal marrow responsiveness to erythropoietin in patients with the anemia of malignancy. In the current proposal, serum erythropoietin levels and bone marrow response to erythropoietin will be studied in patients with various forms of malignancy. Bone marrow response to erythropoietin will be evaluated by measuring Fe59-heme synthesis 3 days following the addition of purified erythropoietin to patient bone marrow cells cultured in a fortified medium. In the current study I propose to; (1) define the natural history and determine clinical significance of marrow hyporesponsiveness to erythropoietin in malignancy, (2) study the cellular mechanisms responsible for the marrow insensitivity to erythropoietin, and (3) clarify the status of serum erythropoietin levels in malignancy.